Although the present specification is directed primarily to breast tumors, the invention disclosed and claimed herein can be used in the treatment and prevention of solid tumors in general, as set forth hereafter.
Breast cancer incidence has increased substantially in the last 10 years, and is the single leading cause of death for women ages 40-49 years in the United States. In 2001, 192,000 cases and 40,000 deaths made breast cancer the most common cancer, after superficial skin cancers, and the second leading cause of cancer death (Lacey et al., Environ Mol Mutagen, 39(2-3):82-88 (2002)).
The development of a breast cancer is a complex process involving a combination of factors, such as environmental and genetic factors. One extensively studied breast tumor model is the chemically induced rat mammary carcinogenesis model (Refs. 9, 18, 19, 39, 54). Chemically induced mammary tumorigenesis in rats is the model most closely resembling a human cancer (40).
Chemically induced rat mammary carcinogenesis typically is achieved by administration of 7,12-dimethylbenzene(a)anthracene (DMBA) (37) or N-methylnitrosourea (MNU) (37). Tumors induced by DMBA or MNU have different morphological characteristics. In particular, tumors induced by MNU are more localized at the breast and are less likely to metastasize (25). Therefore, MNU often is chosen as the chemical agent for the specific induction of breast tumors in rats. These breast tumors can be benign with fibroadenomas and papillomas, or they can be malignant (54). Rats have six pairs of mammary glands, one in the cervical region, two in the thoracic region, one in the abdominal region, and two in the ingual region (4, 54). Virgin rats treated with MNU develop more tumors in the thoracic region than the abdominal region (41).
The development of tumor vasculature has been studied extensively. Tumors greater than a few millimeters in size require a constant nutrient supply, and, therefore, have their own vascular bed and blood flow (10). Recruitment of new vasculature from preexisting blood vessels is termed “angiogenesis.” Without constant nourishment from these developing blood vessels, the tumors become hypoxic and subsequently die. Therefore, tumor vasculature has been a target of cancer therapy for a considerable time (10).
Tumor blood vessels develop substantially differently from normal vasculature, and have different properties. Single layered epithelial cells are the first hastily formed tumor blood vessels. It has been suggested that these blood vessels are recruited when the tumor secretes certain growth factors, like vascular endothelial growth factor (VEGF), in response to hypoxic conditions (23). These newly formed tumor blood vessels do not have a smooth muscle layer or innervation (29, 36, 57).
Tumors also incorporate mature blood vessels that possess all their autoregulatory functions (29). Normal tissue vascular tone is governed by a host of endogenous factors like H+, K+, Ca2+, pO2, pCO2, nitric oxide (NO), as well as other regulatory substances like endothelin (ET-1) (24, 46).
ET-1 is a potent vasoconstrictor and contributes significantly in regulating vascular tone (61). In breast cancer tissue, ETB receptors are found on stromal fibroblast cells (5, 34). Endothelins have been found to be mitogenic to fibroblasts (53), melanocytes, vascular smooth muscle, and endothelium (3, 35, 52). Investigators have shown an increase in ET-1, ET-3, and ETB receptor expression in breast carcinomas (1). It has been shown that both ET-1 and ET-3 cause an increase in VEGF, which is an important angiogenic factor (35). Thus, an increase in ET-1 promotes tumor growth. Several studies have reported an increase in ET-1 levels in breast tumors (1, 21, 31, 33, 59, 60).
The present invention is directed to the effect of endothelin antagonists and endothelin agonists on systemic hemodynamics and blood circulation in solid tumor tissues. The present invention also is directed to the use of endothelin agonists and endothelin antagonists in the treatment of solid tumors.